Gemifloxacin Process and Polymorphs

ABSTRACT

The present invention provides a novel process for the preparation of gemifloxacin and its pharmaceutically acceptable acid addition salts in high yield. The present invention also relates to novel polymorphs of gemifloxacin free base and its hydrates to the processes for their preparation and to pharmaceutical compositions comprising them. The present invention also relates to infusion solutions of gemifloxacin and to processes for their preparation. Thus, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid is reacted with a mixture of acetic anhydride, acetic acid and boric acid to give borane compound, which is then treated with 4-Aminomethyl-3-methoxyimino-pyrrolidinium dimethanesulfonate in presence of triethylamine, followed by treatment with 3.5% sodium hydroxide solution to give gemifloxacin free base.

FIELD OF THE INVENTION

The present invention provides a novel process for the preparation ofgemifloxacin and its pharmaceutically acceptable acid addition salts inhigh yield. The present invention also relates to novel polymorphs ofgemifloxacin free base and its hydrates to the processes for theirpreparation and to pharmaceutical compositions comprising them. Thepresent invention also relates to infusion solutions of gemifloxacin andto processes for their preparation.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,633,262 disclosed a novel quinoline(naphthyridine)carboxylic acid derivatives and pharmaceutically acceptable saltsthereof. These compounds are antibacterial agents. Among themgemifloxacin, chemically7-[3-(Aminomethyl)-4-(methoxyimino)-1-prrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid is a third generation fluorinated quinolone antibacterial agent.Gemifloxacin is represented by the following structure:

Processes for the preparations of gemifloxacin and related compoundswere disclosed in U.S. Pat. No. 5,633,262 and PCT Patent Publication No.WO 01/18002 A1.

One object of the present invention is to provide a novel process forpreparing gemifloxacin and pharmaceutically acceptable acid additionsalts of gemifloxacin in high yield using novel intermediates.

Another object of the present invention is to provide a process for thepreparation of amorphous gemifloxacin.

Another object of the present invention is to provide novel hydrates ofgemifloxacin, processes for preparing them and pharmaceuticalcompositions comprising them.

Another object of the present invention is to provide a novelcrystalline gemifloxacin lactic acid salt, process for preparing it anda pharmaceutical composition comprising it.

Another object of the present invention is to provide a novelcrystalline gemifloxacin formic acid salt, process for preparing it anda pharmaceutical composition comprising it.

Another object of the present invention is to provide a process for thepreparation of infusion solutions of gemifloxacin.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of the present invention, there is provided anovel process for preparing gemifloxacin of formula I:

or a pharmaceutically acceptable salt thereof: which comprises:

-   a) reacting    7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic    acid of formula II:

-   -   with boric acid of formula III:

-   -   in presence of acetic anhydride and acetic acid to give borane        compound of formula IV:

-   5 b) reacting the borane compound of formula IV with    4-aminomethyl-3-methoxyimino-pyrrolidine of formula V:

-   -   to give the compound of formula VI:

-   c) treating the compound of formula VI with an alkaline metal    hydroxide, carbonate or bicarbonate to obtain gemifloxacin of    formula I and optionally converted gemifloxacin formed into a    pharmaceutically acceptable acid addition salts of gemifloxacin.

Borane compound of the formula IV and VI are novel and forms part of theinvention.

Preferably the reaction in step (a) is carried out at about 30° C. toreflux temperature more preferably at about 80° C. to reflux temperatureand still more preferably at reflux temperature.

Preferably, the borane compound of formula IV formed is isolated assolid by conventional means.

Preferably the reaction in step (b) is carried out at about 15-100° C.,more preferably at about 30-80° C. and still more preferably at about50-60° C.

Preferably the reaction in step (b) is carried out in a solvent selectedfrom hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane;chlorinated hydrocarbon solvents such as methylene chloride, ethylenechloride and chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane anda mixture thereof and more preferable solvent is acetonitrile.

The compound of formula V in step (b) may be used as free base or as anacid addition salt form. If the compound of formula V is used as an acidaddition salt, it is preferred to convert the salt to the free basebefore reacting with the compound of formula IV.

Preferable alkaline metal hydroxide used in step (c) is sodium hydroxideor potassium hydroxide; preferable alkaline metal carbonate is sodiumcarbonate or potassium carbonate; and preferable alkaline metalbicarbonate is sodium bicarbonate or potassium bicarbonate. Morepreferable alkaline metal hydroxide is aqueous sodium hydroxide.

The compounds of formulae II and V are known and can be obtained fromknown procedures.

According to another aspect of the present invention, there is provideda process for preparation of amorphous gemifloxacin, which comprises:

-   a) preparing a solution of gemifloxacin in dimethyl formamide or    methylene chloride; and-   b) isolating amorphous gemifloxacin from the solution.

The amorphous gemifloxacin is characterized by having broad X-raydiffraction spectrum as in FIG. 1.

The isolation may be initiated by a method usually known in the art suchas cooling, seeding, partial removal of the solvent from the solution,addition of precipitating solvent or a combination thereof.

Preferably, isolation may be carried out by cooling or by using aprecipitating solvent to obtain amorphous gemifloxacin. Typical X-raydiffraction spectrum of amorphous gemifloxacin is shown in FIG. 1.

According to another aspect of the present invention, there is provideda novel gemifloxacin hemihydrate.

According to another aspect of the present invention, a process isprovided for preparation of gemifloxacin hemihydrate, which comprisesdrying wet gemifloxacin at 40-100° C., preferably at 50-70° C. till thewater content is reduced to 1.8-2.4% by weight. The control on thedrying is required for the product not to be contaminated with otherhydrate forms of gemifloxacin or anhydride gemifloxacin.

According to another aspect of the present invention, there is provideda novel crystalline gemifloxacin monohydrate;

According to another aspect of the present invention, a process isprovided for preparation of gemifloxacin monohydrate, which comprisesdrying wet gemifloxacin at 40-100° C., preferably at 50-70° C. till thewater content is reduced to 4.0-5.0% by weight. The control on thedrying is required for the product not to be contaminated with otherhydrate forms of gemifloxacin or anhydride gemifloxacin.

According to another aspect of the present invention, a process isprovided for preparation of gemifloxacin sesquihydrate, which comprisesdrying wet gemifloxacin at 40-100° C., preferably at 50-70° C. till thewater content is reduced to 5.8-6.5% by weight. The control on thedrying is required for the product not to be contaminated with otherhydrate forms of gemifloxacin or anhydride gemifloxacin.

The gemifloxacin hemihydrate, gemifloxacin monohydrate, gemifloxacinsesquihydrate may be converted to amorphous gemifloxacin using thehydrates as starting materials in the process for preparing amorphousgemifloxacin.

The wet gemifloxacin may be obtained by crystallizing gemifloxacin fromaqueous medium.

According to another aspect of the present invention, there is provideda novel crystalline form of gemifloxacin lactic acid salt, designated asgemifloxacin lactate, characterized by an x-ray powder diffractionspectrum having peaks expressed as 2θ at about 7.4, 7.7, 8.2, 9.1, 12.4,18.5, 19.8, 23.6, 25.7 and 26.8 degrees. FIG. 2 shows typical X-raypowder diffraction spectrum of gemifloxacin lactate.

According to another aspect of the present invention, a process isprovided for preparation of gemifloxacin lactate, which comprisescontacting gemifloxacin with lactic acid. Preferably lactic acid or asolution of lactic acid is added to a solution of gemifloxacin.Gemifloxacin lactate may be isolated as a crystalline solid byconventional means.

The solvent used for preparing the solution of gemifloxacin is selectedfrom the group consisting of chlorinated hydrocarbon solvents such asmethylene chloride, ethylene chloride and chloroform, alcoholic solventssuch as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and amixture thereof. More preferable solvent is methylene chloride, ethanoland a mixture thereof.

According to another aspect of the present invention, there is provideda novel crystalline form of gemifloxacin formic salt, designated asgemifloxacin formate.

According to another aspect of the present invention, a process isprovided for preparation of gemifloxacin formate, which comprisescontacting gemifloxacin with formic acid. Preferably formic acid or asolution of formic acid is added to a solution of gemifloxacin.Gemifloxacin formate may be isolated as a crystalline solid byconventional means.

The solvent used for preparing the solution of gemifloxacin is selectedfrom the group consisting of chlorinated hydrocarbon solvents such asmethylene chloride, ethylene chloride and chloroform, alcoholic solventssuch as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol anda mixture thereof. More preferable solvent is methylene chloride,ethanol and a mixture thereof.

The novel gemifloxacin hydrates may be used in pharmaceuticalpreparations. The pharmaceutical applications of gemifloxacin and itssalts are described in U.S. Pat. No. 5,633,262 and PCT patentpublication No. WO 01/18002 A1, which are incorporated here in byreference.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline gemifloxacinhemihydate and a pharmaceutically acceptable carrier.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline gemifloxacinmonohydate and a pharmaceutically acceptable carrier.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline gemifloxacinsesquihydate and a pharmaceutically acceptable carrier.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline gemifloxacin lactateand a pharmaceutically acceptable carrier.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline gemifloxacin formateand a pharmaceutically acceptable carrier.

According to another aspect of the present invention, there is providedinfusion solutions of gemifloxacin which contain 0.015 to 0.5 gm ofgemifloxacin per 100 ml of aqueous solution and an amount of aphysiologically tolerated acid which suffices to dissolve thegemifloxacin and to stabilize the solution and, where appropriate,customary formulating auxiliaries.

Preferably, the infusion solutions contain an amount of physiologicallytolerated acid, which suffices to dissolve the gemifloxacin and tostabilize the solution, of one or more acid(s) from the group comprisinghydrochloric acid, methanesulfonic acid, propionic acid, succinic acid,glutaric acid, citric acid, fumaric acid, maleic acid, tartaric acid,glutamic acid, gluconic acid, glucuronic acid, galacturonic acid,ascorbic acid, phosphoric acid, nitric acid, acetic acid, maleic acid,L-aspartic acid and lactic acid.

Preferable physiologically tolerated acid is lactic acid, hydrochloricacid or a mixture thereof. More preferable physiologically toleratedacid is lactic acid.

More preferably, the infusion solutions which contain 0.015 to 0.5 gm ofthe gemifloxacin per 100 ml of aqueous solution and, depending on thegemifloxacin concentration, up to 5.0 moles, in particular 0.9 to 5.0moles, and particularly preferably 1.04 to 2.20 moles, relative to 1mole of gemifloxacin, of one or more physiologically tolerated acids,and where several acids are present their total content does not exceedthe amount of 5.0 moles, relative to 1 mole of gemifloxacin.

The infusion solutions according to the invention have a pH of 3.0 to5.2. pH values from 3.6 to 4.7 and 3.9 to 4.5 are preferred. pH valuesin the range from 4.1 to 4.3 are very particularly preferred.

The particularly preferable infusion solution of gemifloxacin which,apart from gemifloxacin, water and other formulating auxiliaries,contain, depending on the amount of gemifloxacin, 0.99 to 1.50 moles,preferably 1.04 to 1.40 moles, of lactic acid and 0.0 to 0.80 moles ofhydrochloric acid (in each case relative to 1 mole of gemifloxacin),and, relative to 100 ml of solution, 0.6 to 2.2 g of NaCl, preferably0.75 to 1.20 gm, in particular 0.85 to 0.95 g of NaCl. The solutionsthus obtained have osmolalities which differ according to the amount ofsodium chloride and gemifloxacin concentration. The osmolalitiesrelating to the amounts of sodium chloride listed above are 0.2 to 0.7,0.26 to 0.39 and 0.28 to 0.32 Osm/Kg of solution respectively.Corresponding values can also be adjusted using other isotonicizingagents or mixtures thereof, as indicated above. Depending on thegemifloxacin and acid concentration, small differences from theseosmolalities are perfectly possible.

The infusion solutions according to the invention can be in the form ofdosage units, suitable for infusion, with removable contents of 40 to600 ml, preferably 50 to 120 ml.

According to another aspect of the present invention, a process isprovided for preparation of infusion solutions, which comprises mixing asuitable amount of the gemifloxacin, where appropriate in the form of asalt, such as an alkali metal or alkaline earth metal salt or additionsalt, of a hydrate or of a hydrate of the salt, or in the form ofmixtures of these salts or hydrates, with the amount of aphysiologically tolerated acid or of a mixture of severalphysiologically tolerated acids which, in relation to the amount whichjust suffices to dissolve the gemifloxacin or its salts or hydrates,represents an excess preventing separation out of the gemifloxacin,adding, where appropriate, formulating auxiliaries, and making up withwater or a customary infusion vehicle solutions in such a manner thatthe concentration of the gemifloxacin is adjusted to the range from0.015 to 0.5 gm.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows typical X-ray powder diffraction spectrum of amorphousgemifloxacin.

FIG. 2 shows typical X-ray powder diffraction spectrum of crystallinegemifloxacin lactate.

X-Ray powder diffraction spectrum was measured on a Bruker axs D8advance x-ray powder diffractometer having a Copper-Kα radiation.Approximately 1 gm of sample was gently flattened on a sample holder andscanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta perstep and a step time of 0.5 seconds. The sample was simply placed on thesample holder. The sample was rotated at 30 rpm at a voltage 40 KV andcurrent 35 mA.

The invention will now be further described by the following example,which is illustrative rather than limiting.

EXAMPLE 1

Acetic anhydride (35.5 ml) and acetic acid (16.5 ml) are added to boricacid (3.5 gm), heated to reflux and then the contents are stirred for 3hours at the same temperature.7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (27 gm) is added to the reaction mass and refluxed for 2 hours.Then toluene (200 ml) is added, cooled to 25-30° C. and distilled offthe solvent under vacuum. Again toluene (200 ml) is added to thereaction mass, cooled to 5-10° C. and the separated solid is filteredand dried to give 38 gm of borane compound of formula IV (HPLC Purity:90%).

To the suspension of 4-Aminomethyl-3-methoxyimino-pyrrolidiniumdimethanesulfonate (63.5 gm) in acetonitrile (125 ml) is addedtriethylamine (75 gm) and stirred for 30 minutes at 25-30° C. and thenadded borane compound (obtained above) to the contents. The contents areheated to 50-60° C. and stirred for 4 hours at the same temperature.Then distilled off the solvent under reduced pressure, cooled to 25-30°C., water (350 ml) is added and stirred for 10 minutes at 25-30° C.Filtered the compound and washed with water (50 ml). To the compoundacetonitrile (100 ml) and 3.5% sodium hydroxide solution (250 ml) areadded and stirred for 1 hour to form a clear solution. Then the pH ofthe solution is adjusted to 3.4 with 1N hydrochloric acid (25 ml) andthe separated solid is stirred for 15 minutes. Filtered the material,washed with water (60 ml) to obtain wet gemifloxacin (HPLC purity:99.8%).

The wet gemifloxacin is dried at 50-55° C. to constant weight to obtain31.6 gm anhydride gemifloxacin free base (HPLC Purity: 99.7%).

EXAMPLE 2

Anhydride gemifloxacin free base (10 gm, obtained in example 1) is addedto dimethylformamide (300 ml) at 25-35° C., the contents are heated to75-80° C. and stirred for 1 hours at the same temperature to form aclear solution. The reaction mass is cooled to 25-35° C. Then theseparated solid is filtered, washed with diisopropyl ether (50 ml) anddried at 50-55° C. to give 5.2 gm of amorphous gemifloxacin free base(HPLC Purity: 99.92%).

EXAMPLE 3

Gemifloxacin free base (3 gm) is added to methylene dichloride (450 ml)and stirred for 20 minutes at the 25-35° C. to form a clear solution.Then added diisopropyl ether (900 ml) and stirred for 1 hour at the sametemperature. The reaction mass is cooled to 10° C. Then stirred for 10minutes at 10-15° C. and the separated solid is filtered, washed withdiisopropyl ether (15 ml) and dried at 50-55° C. for 2 hours to give 2gm of amorphous gemifloxacin free base (HPLC Purity: 99.8%).

EXAMPLE 4

Gemifloxacin free base (3 gm) is added to methylene dichloride (65 ml)at 25-30° C., ethanol (20 ml) is added to form a clear solution. To thesolution, lactic acid (0.6 ml) is added at 25-30° C., stirred for 1 hourand then cooled to 10° C. Filtered the solid and dried at 50-55° C. togive 3 gm of gemifloxacin lactate (HPLC Purity: 99.93%).

EXAMPLE 5

Gemifloxacin free base (3 gm) is added to methylene dichloride (65 ml)at 25-30° C., ethanol (20 ml) is added to form a clear solution. To thesolution, formic acid (0.4 ml) is added at 25-30° C., stirred for 1 hourand then cooled to 10° C. Filtered the solid and dried at 50-55° C. togive 2.6 gm of gemifloxacin formate (HPLC Purity: 99.93%).

EXAMPLE 6

The wet gemifloxacin (2 gm obtained in example 1) is dried under vacuumat 50-55° C. until the water content is reduced to 2.0% to obtaingemifloxacin hemihydrate (HPLC Purity: 99.92%).

EXAMPLE 7

The wet gemifloxacin (2 gm obtained in example 1) is dried under vacuumat 50-55° C. until the water content is reduced to 4.8% to obtaingemifloxacin monohydrate (HPLC Purity: 99.90%).

EXAMPLE 8

The wet gemifloxacin (2 gm obtained in example 1) is dried under vacuumat 50-55° C. until the water content is reduced to 6.1% to obtaingemifloxacin sesquihydrate (HPLC Purity: 99.93%).

EXAMPLE 9

The compositions of gemifloxacin infusion solution is as follows.

Formulation Composition Gemifloxacin 70 mg Lactic acid 20% (w/w) 144.3mg Hydrochloric acid 1.5 mg Sodium chloride 5.4 gm Water 600.0 ml pHapprox. 4.3 Osm: approx. 0.29 Osm/kg

1. A process for the preparation of gemifloxacin of the formula I:

or a pharmaceutically acceptable salt thereof: which comprises: a)reacting7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid of the formula II:

with boric acid of the formula III:

in the presence of acetic anhydride and acetic acid to give a boranecompound of the formula IV:

b) reacting the borane compound of the formula IV with4-aminomethyl-3-methoxyimino-pyrrolidine of the formula V:

to give the compound of formula VI:

c) and treating the compound of formula VI with an alkaline metalhydroxide, carbonate or bicarbonate to obtain gemifloxacin of theformula I and optionally converting the gemifloxacin formed into apharmaceutically acceptable acid addition salt of gemifloxacin.
 2. Theprocess according to claim 1, wherein the reaction in step (a) iscarried out at about 30° C. to the reflux temperature.
 3. The processaccording to claim 2, wherein the reaction is carried out at about 80°C. to the reflux temperature.
 4. The process according to claim 3,wherein the reaction is carried out at the reflux temperature.
 5. Theprocess according to claim 1, wherein the reaction in step (b) iscarried out in a solvent selected from hydrocarbon solvents, chlorinatedhydrocarbon solvents, acetonitrile, tetrahydrofuran, 1,4-dioxane and amixture thereof.
 6. The process according to claim 5, wherein thesolvent is n-hexane, cyclohexane, n-heptane, methylene chloride or1,4-dioxane.
 7. The process according to claim 6, wherein the solvent isacetonitrile.
 8. The process according to claim 1, wherein the reactionin step (b) is carried out at about 15-100° C.
 9. The process accordingto claim 8, wherein the reaction in step (b) is carried out at about30-80° C.
 10. The process according to claim 9, wherein the reaction instep (b) is carried out at about 50-60° C.
 11. The process according toclaim 1, wherein the alkaline metal hydroxide is sodium hydroxide orpotassium hydroxide, the alkaline metal carbonate is sodium carbonate orpotassium carbonate, and the alkaline metal bicarbonate is sodiumbicarbonate or potassium bicarbonate.
 12. The process according to claim11, wherein the alkaline metal hydroxide is sodium hydroxide.
 13. Aprocess for the preparation of amorphous gemifloxacin, which comprises:a) preparing a solution of gemifloxacin in dimethylformamide ormethylene chloride; and b) isolating amorphous gemifloxacin from thesolution.
 14. The process according to claim 13, wherein the isolationof amorphous gemifloxacin is performed by techniques such as cooling,seeding, partial removal of the solvent from the solution, addition of aprecipitating solvent or a combination thereof.
 15. The processaccording to claim 14, wherein the isolation is performed by cooling.16. The process according to claim 14, wherein the isolation isperformed by using a precipitating solvent.
 17. The process according toclaim 16, wherein the precipitating solvent is diisopropyl ether.
 18. Acompound of the formula IV:


19. A compound of the formula VI:


20. Gemifloxacin hemihydrate.
 21. A process for the preparation ofgemifloxacin hemihydrate of claim 20, which comprises drying wetgemifloxacin at 40-100° C. until the water content is reduced to1.8-2.4% by weight.
 22. The process according to claim 21, wherein thedrying is carried out at 50-70° C.
 23. Gemifloxacin monohydrate.
 24. Aprocess for the preparation of the gemifloxacin monohydrate of claim 23,which comprises drying wet gemifloxacin at 40-100° C. until the watercontent is reduced to 4.0-5.0% by weight.
 25. The process according toclaim 24, wherein the drying is carried out at 50-70° C. 26.Gemifloxacin sesquihydrate.
 27. A process for the preparation of thegemifloxacin sesquihydrate of claim 26, which comprises drying wetgemifloxacin at 40-100° C. till the water content is reduced to 5.8-6.5%by weight.
 28. The process according to claim 27, wherein the drying iscarried out at 50-70° C.
 29. A crystalline gemifloxacin lactate,characterized by an X-ray powder diffraction spectrum having peaksexpressed as 2θ at about 7.4, 7.7, 8.2, 9.1, 12.4, 18.5, 19.8, 23.6,25.7 and 26.8 degrees.
 30. A process for the preparation of thecrystalline gemifloxacin lactate of claim 29, which comprises contactinggemifloxacin with lactic acid in a solvent medium and crystallizing thegemifloxacin lactate from the solution.
 31. The process according toclaim 30, wherein the solvent is selected from a chlorinated hydrocarbonsolvent, alcoholic solvent and a mixture thereof.
 32. The processaccording to claim 31, wherein the chlorinated hydrocarbon solvents aremethylene chloride, ethylene chloride, chloroform and a mixture thereof.33. The process according to claim 32, wherein the chlorinatedhydrocarbon solvent is methylene chloride.
 34. The process according toclaim 31, wherein the alcoholic solvent is methanol, ethanol, isopropylalcohol, tert-butyl alcohol and a mixture thereof.
 35. The processaccording to claim 34, wherein the alcoholic solvent is ethanol. 36.Crystalline gemifloxacin formate.
 37. A process for the preparation ofthe crystalline gemifloxacin formate of claim 36, which comprisescontacting gemifloxacin with formic acid in a solvent medium andcrystallizing the gemifloxacin formate from the solution.
 38. Theprocess according to claim 37, wherein the solvent is selected from achlorinated hydrocarbon solvent, alcoholic solvent and a mixturethereof.
 39. The process according to claim 38, wherein the chlorinatedhydrocarbon solvent is methylene chloride, ethylene chloride, chloroformand a mixture thereof.
 40. The process according to claim 39, whereinthe chlorinated hydrocarbon solvent is methylene chloride.
 41. Theprocess according to claim 38, wherein the alcoholic solvent ismethanol, ethanol, isopropyl alcohol, tert-butyl alcohol and a mixturethereof.
 42. The process according to claim 41, wherein the alcoholicsolvent is ethanol.
 43. A pharmaceutical composition comprisinggemifloxacin hemihydrate and a pharmaceutically acceptable excipient.44. A pharmaceutical composition comprising gemifloxacin monohydrate anda pharmaceutically acceptable excipient.
 45. A pharmaceuticalcomposition comprising gemifloxacin sesquihydrate and a pharmaceuticallyacceptable excipient.
 46. A pharmaceutical composition comprisingcrystalline gemifloxacin lactate and a pharmaceutically acceptableexcipient.
 47. A pharmaceutical composition comprising crystallinegemifloxacin formate and a pharmaceutically acceptable excipient.
 48. Anaqueous infusion solution comprising 0.015 to 0.5 gm of gemifloxacin per100 ml of aqueous solution and an amount of at least one physiologicallytolerated acid which suffices to dissolve the gemifloxacin, whereinthere are about 1.33 to 2.2 moles per mole of gemifloxacin, of thephysiologically tolerated acid.
 49. An infusion solution according toclaim 48, wherein the physiologically tolerated acid is selected fromthe group consisting of hydrochloric acid, methanesulfonic acid,propionic acid, succinic acid, glutaric acid, citric acid, fumaric acid,maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronicacid, galacturonic acid, ascorbic acid, phosphoric acid, nitric acid,acetic acid, maleic acid, L-aspartic acid, lactic acid and a mixturethereof.
 50. An infusion solution according to claim 49, wherein thephysiologically tolerated acid is lactic acid, hydrochloric acid or amixture thereof.
 51. An infusion solution according to claim 50, whereinthe physiologically tolerated acid is lactic acid.
 52. An infusionsolution according to claim 51, wherein the lactic acid is present inabout 1.33 to 1.50 moles per mole of gemifloxacin.
 53. An infusionsolution according to claim 48, having a pH from 3.0 to 5.2.
 54. Aninfusion solution according to claim 53, having a pH from 3.6 to 4.7.55. An infusion solution according to claim 54, having a pH from 3.9 to4.5.
 56. An infusion solution according to claim 55, having a pH from4.1 to 4.3.
 57. An infusion solution according to claim 48, which issubstantially isotonic.
 58. An infusion solution according to claim 48,containing 1.33 to 2.2 moles of lactic acid and 0.0 to 0.80 moles ofhydrochloric acid per mole of gemifloxacin, and relative to 100 ml ofsolution, 0.6 to 2.2 gm of NaCl.